<strong>Chapter 1</strong> Provides an overview of drug discovery with particular emphasis on library selection and hit identification methods using virtual based approaches. <strong>Chapter 2</strong> Gives an outline of the bone morphogenetic protein (BMP) signalling pathway and literature BMP pathway modulators. The association between the regulation of BMP pathway and cardiomyogenesis is also described. <strong>Chapter 3</strong> Describes the use of ligand based virtual screening to discover small molecule activators of the BMP signalling pathway. A robust cell based BMP responsive gene activity reporter assay was developed to test the libraries of small molecules selected. Hit molecules from the screen were synthesised to validate activity. It was found that a group of known histone deacetylase (HDAC) inhibitors displayed most promising activity. These were evaluated in a secondary assay measuring the expression of two BMP pathway regulated genes, hepcidin and Id1, using reverse transcription polymerase chain reaction (RT-PCR). 188 was discovered to increase expression of both BMP-responsive genes. <strong>Chapter 4</strong> Provides an overview of existing cannabinoid receptor (CBR) modulating molecules and their connection to progression of atherosclerosis. <strong>Chapter 5</strong> Outlines the identification and optimisation of selective small molecule agonists acting at the cannabinoid 2 receptor (CB₂R). Ligand based virtual screen was undertaken and promising hits were synthesised to allow structure activity relationship (SAR) to be developed around the hit molecule providing further information of the functional groups tolerated at the active site. Subsequent studies led to the investigation and optimisation of physicochemical properties around 236 leading to the development of a suitable compound for in vivo testing. Finally, a CB₂R selective compound with favourable physicochemical properties was evaluated in vivo in a murine inflammation model and displayed reduced recruitment of monocytes to the site of inflammation.

In recent years, the potential benefits of high-throughput virtual screening to the drug discovery community have been recognized, bringing an increase in the number of tools developed for this purpose. These programs have to process large quantities of data, searching for an optimal solution in a vast combinatorial range. This is particularly the case for protein-ligand docking, since proteins are sophisticated structures with complicated interactions for which either molecule might reshape itself. Even the very limited flexibility model to be considered here, using ligand conformation ensembles, requires six dimensions of exploration - three translations and three rotations - per rigid conformation. The functions for evaluating pose suitability can also be complex to calculate. Consequently, the programs being written for these biochemical simulations are extremely resource-intensive. This work introduces a pure computer science approach to the field, developing techniques to improve the effectiveness of such tools. Their architecture is generalized to an abstract pattern of nested layers for discussion, covering scoring functions, search methods, and screening overall. Based on this, new stratagems for molecular docking software design are described, including lazy or partial evaluation, geometric analysis, and parallel processing implementation. In addition, a range of novel algorithms are presented for applications such as active site detection with linear complexity (PIES) and small molecule shape description (PASTRY) for pre-alignment of ligands. The various stratagems are assessed individually and in combination, using several modified versions of an existing docking program, to demonstrate their benefit to virtual screening in practical contexts. In particular, the importance of appropriate precision in calculations is highlighted.

在過去幾十年的時間，西方國家逐漸興起華文熱。拉丁美洲則到2000年代才漸漸開始看到越來越多的華語課程，因此如今華語教學在此地區仍處於一個不斷變化的階段。在阿根廷，由於華語教師以及華語教材的需求日益增長，當地的華語教師經常必須自備教材或是遷就於不適合的教材。筆者在阿根廷實際從事過華語職業教師數年，於此時期內發現當地使用的對外華語教學教材之理念與教學的實際做法之間存在明顯的差異性。筆者在教學中發現阿根廷學習者具有獨特的語言學習需求與習慣，因此教學法應該迎合學習者的特色與需求。如今阿根廷的華語教學界裡所面臨的問題涉及以下三方面：一是要如何滿足學員的需求、再者是要如何迎合當地學員的語言學習習慣與當地華語教師所使用的教學法、三是要如何突破教目前所使用的教材之無相關性和無效性。目前阿根廷的華語學習者所使用的教材中，有一半是以英語編寫，主要對象是以英語為母語者。另一半是來自中華人民共和國，並以西班牙文編寫的教材。在2009年間，當地的教師出版了一本號稱針對拉丁美洲華語學習者所寫得教材，但是本教材在教學品質及內容相關性皆有缺失。雖然這些教材在阿根廷被廣泛使用，然而對於當地學習者而言卻稱不上是最理想的教材。阿根廷目前所使用的教材主要的缺失，首先在於議題和語言內容與學習者的生活毫無相關。再者，此類教材的設計與教學法不符合當地學習者的需求。最後，教材所採用的練習題無法激勵學習者的思考和溝通能力。本研究的目的為初步分析阿根廷目前所使用的華語教材，並探討其實用性(或有效性)及相關性。藉由了解學習者的需求和當地教師們對於教材的意見，筆者將提出較有效的教學法和相稱的教材。本論文結合了筆者本人在阿根廷教學的實務經驗和當地學習者之意見。在經過教材分析後，筆者以最適合當地華語學習者的溝通教學法(特別採用溝通性教學法)設計出一個課程單元教案，希冀能提升往後西班牙語為母語者的華語學習效果，並對推動區域化華語文教材的編制能有些許貢獻。 / In the past decade, most countries of the Western hemisphere witnessed the surge of the “Chinese Language Fever”. Such a wave arrived in Latin America in mid 2000, with the emergence of Chinese language courses. At present, the teaching of Chinese as a foreign language in this part of the world is still at an early stage of development. In Argentina, the need for qualified Chinese teachers as well as adequate teaching materials is nowadays most urgent, as local teachers find themselves having to adjust to available teaching materials, or in need of preparing additional teaching material to compensate for the shortcomings of currently used course books. During my years as a teacher of Chinese in Argentina, I realized that the underpinnings of the Chinese pedagogical materials are in stark contrast with the practices in the actual classroom. Through my teaching it became apparent that Argentine learners possess distinctive language learning habits and needs, which had to be catered for by means of a suitable teaching methodology. In order to improve the current situation, teachers of Chinese in Argentina must seriously address the following three questions: How should learners’ needs be addressed? How should we reconcile the discrepancy between teaching methodologies and students’ language learning habits? And lastly, how should we reconcile the lack of relevance and effectiveness of Chinese teaching materials? At the moment, half of the materials used by local learners are written in English, i.e. with an English speaking learner in mind. The other half is published in the People’s Republic of China with explanations and instructions written in Spanish. Although circa 2009 a book published by local teachers emerged claiming to be designed specifically for the Latin American learner, the pedagogical quality and relevance of the content are highly questionable. Although these materials are widely used in Argentina, they are far from being ideal for the local learner. The main flaws of Chinese teaching materials currently used in Argentina are namely, the lack of relevance of the themes and linguistic content with respect to the learner’s world experience, and last, but not least, the failure of the practice activities to encourage significant intellectual processes and the development of communicational skills. The aim of this research is, therefore, to analyze the pedagogical materials currently in use in Argentina, in order to evaluate their effectiveness and relevance. In view of the needs revealed by local learners and the opinions of Chinese teachers in said country, I intend to propose a more adequate methodology, as well as a set of sample materials. Thus the present paper is the result of my personal experience as a teacher of Chinese in Argentina and the integration of the opinions of local Chinese language learners. After having analyzed the materials currently available, I will present a set of sample materials, in the hope that it will contribute to the improvement of the quality of the Chinese learning process for Spanish speakers, as well as to promote the future development of localized Chinese teaching materials.

This thesis presents the development and redesign of a commercial electrochemical quartz crystal microbalance with dissipation (E–QCM–D). This was used to study factors affecting the efficiency of the four electron reduction catalysed by the fuel cell enzyme bilirubin oxidase from Myrothecium verrucaria immobilised on thiol modified gold surfaces. Within this thesis, the E–QCM–D was used to show that application of a constant potential to bilirubin oxidase adsorbed to thiol-modified gold surfaces causes activity loss that can be attributed to a change in structural arrangement. Varying the load by potential cycling distorts the enzyme by inducing rapid mass loss and denaturation. Attaching the enzyme covalently reduces the mass loss caused by potential cycling but does not mitigate activity loss. Covalent attachment also changes the orientation of the surface bound enzyme as verified by the position of the catalytic wave (related to the overpotential for catalysis) and reactive labelling followed by mass spectrometry analysis. The E–QCM–D was used to show how electrostatic interactions affect enzyme conformation where high pH causes a reduction in both mass loading at the electrode and a reduction in activity. At pH lower than the enzyme isoelectric point, there is a build up of multilayers in a clustered adsorption. When enzyme adsorbs to hydrophobic surfaces there is a rapid denaturation which completely inactivates the enzyme. Changing the surface chemistry from carboxyl groups to hydroxyl and acetamido groups shows that catalysis is shifted to more negative potentials as a result of an enzyme misorientation. Further to this, increasing the chain length of the thiol modifier indicates that an increased distance between surface and enzyme reduces activity, enzyme loading and results in a conformational rearrangement that permits electron transfer over longer distances.

<p>Recent advances in sensor technologies and data acquisition platforms have led to the era of Big Data. The rapid growth of artificial intelligence (AI), computing power and machine learning (ML) algorithms allow Big Data to be processed within affordable time constraints. This opens abundant opportunities to develop novel and efficient approaches to enhance the sustainability and resilience of Smart Cities. This work, by starting with a review of the state-of-the-art data fusion and ML techniques, focuses on the development of advanced solutions to structural health monitoring (SHM) and metamaterial design and discovery strategies. A deep convolutional neural network (CNN) based approach that is more robust against noisy data is proposed to perform structural response estimation and system identification. To efficiently detect surface defects using mobile devices with limited training data, an approach that incorporates network pruning into transfer learning is introduced for crack and corrosion detection. For metamaterial design, a reinforcement learning (RL) and a neural network based approach are proposed to reduce the computation efforts for the design of periodic and non-periodic metamaterials, respectively. Lastly, a physics-constrained deep auto-encoder (DAE) based approach is proposed to design the geometry of wave scatterers that satisfy user-defined downstream acoustic 2D wave fields. The robustness of the proposed approaches as well as their limitations are demonstrated and discussed through experimental data or/and numerical simulations. A roadmap for future works that may benefit the SHM and material design research communities is presented at the end of this dissertation.</p><br>

Indiana University-Purdue University Indianapolis (IUPUI) / Topology optimization allows designers to obtain lightweight structures considering the binary distribution of a solid material. The introduction of cellular material models in topology optimization allows designers to achieve significant weight reductions in structural applications. However, the traditional topology optimization method is challenged by the use of cellular materials. Furthermore, increased material savings and performance can be achieved if the material and the structure topologies are concurrently designed. Hence, multi-scale topology optimization methodologies are introduced to fulfill this goal. The objective of this investigation is to discuss and compare the design methodologies to obtaining optimal macro-scale structures and the corresponding optimal meso-scale material designs in continuum design domains. These approaches make use of homogenization theory to establish communication bridges between both material and structural scales. The periodicity constraint makes such cellular materials manufacturable while relaxing the periodicity constraint to achieve major improvements of structural performance. Penalization methods are used to obtain binary solutions in both scales. The proposed methodologies are demonstrated in the design of stiff structure and compliant mechanism synthesis. The multiscale results are compared with the traditional structural-level designs in the context of Pareto solutions, demonstrating benefits of ultra-lightweight configurations. Errors involved in the mult-scale topology optimization procedure are also discussed. Errors are mainly classified as mesh refinement errors and homogenization errors. Comparisons between the multi-level designs and uni-level designs of solid structures, structures using periodic cellular materials and non-periodic cellular materials are provided. Error quantifications also indicate the superiority of using non-periodic cellular materials rather than periodic cellular materials.

In diesem Beitrag wird ein Vergleich zwischen indirekten Testmethoden zur Bewertung der Verbaubarkeit von 3D-gedruckten Mörteln und Betonen vorgestellt. Die Untersuchungen erfolgten an extrudierten Proben von acht zementbasierten Mischungen mit unterschiedlichem rheologischen Verhalten. Auf der Basis der erzielten Ergebnisse werden Vorhersagen zum Material- bzw. Stabilitätsversagen getroffen und mit den Ergebnissen des Direktdruckversuchs verglichen. Anschließend werden die Vor- und Nachteile unterschiedlicher Prüfmethoden diskutiert. Zu diesen zählen die Techniken der Rotationsrheometrie mit konstanter Rotationsgeschwindigkeit (engl.: constant rotational velocity, CRV), ein schneller Penetrationstest sowie einaxiale Druckversuche mit und ohne Querdehnungsbehinderung.

<p>The main goal of this thesis research is to expand the range of unique properties of phase transforming cellular materials (PXCMs), a new class of architected materials, and to extend their applicability both in the engineering disciplines and in the medical field. A novel aspect of PXCMs is their unique energy dissipation during loading via a snapping mechanism associated with a geometric transition between one stable configuration to another stable configuration at the unit cell level. Phase transformation is analogous to displacive transformations, such as martensitic transformations in shape memory alloys, with no change in configurational entropy. To accomplish this goal, three problem areas are addressed with the first exploring the effects of length scale as added structural hierarchy on material properties and energy dissipation, the second providing an analysis of the durability of architected materials via a novel additive manufacturing method, and the third, an extension into the medical field. Two examples are provided that demonstrate the effects of length scale as added structural hierarchy on material properties, and a machine learning approach for the feasible design of materials with additional levels of structural hierarchy is presented. A simple design approach coupled with a novel additive manufacturing method is discussed for the design of architected materials with high durability. Lastly, a concept for de-clogging bile stents via a temperature driven, shape-memory mechanism inspired by peristaltic locomotion in the human esophagus is presented.</p>

As depicted in Chapter I, 2-oxoglutarate- (2OG) dependent oxygenases are ubiquitous in living systems and display a wide range of cellular functions, spanning metabolism, transcription, and translation. Although functionally diverse, the 2OG oxygenases share a high degree of structural similarities between their catalytic sites. From a medicinal chemistry point of view, the combination of biological diversity and structural similarity presents a rather challenging task for the development of selective small molecules for functional studies in vivo. The non-selective metal chelator 8-hydroxyquinoline (8HQ) was used as a template for the generation of tool compound <b>I</b> for the KDM4 subfamily of histone demethylases via application of the Betti reaction. Structural analogue <b>II</b> was used as the corresponding negative control (Figure A). These compounds were characterised in vitro against a range of 2OG oxygenases and subsequently used for studies in cells. <b>I</b> displays selectivity for KDM4 and increases the level of the H3K9me3 histone mark in cells. It has an effect on the post-translational modification pattern of histone H3, but not other histones, and reduces the viability of lung cancer cells, but not normal lung cells, derived from the same patient. <b>I</b> also stabilises hypoxia-inducable factor HIF in cells via a mechanism which seems to be independent from prolyl hydroxylase inhibition. This work is described in Chapters II and III. The chemical biology research in epigenetics is complemented by qualitative analysis conducted in the social sciences at Said Business School. With a global view on how innovation occurs and may actively be fostered, Chapter IV focuses on the potential of epigenetics in drug discovery and how this process may actively be promoted within the framework of open innovation. Areas of focus include considerations of incremental and disruptive technology; how to claim, demarcate, and control the market; how knowledge brokering occurs; and insights about process, management, organisation, and culture of open innovation. In contrast to the open-skies approach adopted for the development of a tool compound in Chapters II and III, a focused-library approach was taken for the generation of a tool compound for the OGFOD1 ribosomal prolyl hydroxylase. The development of a suitable in vitro activity assay for OGFOD1 in Chapter V enabled the development of lead compound <b>III</b> in Chapter VI. <b>III</b> is selective for OGFOD1 against the structurally closely related prolyl hydroxylase PHD2.

The presented diploma thesis was elaborated as an architectural study of a Central European Forum in Olomouc (SEFO). Campus SEFO will be created as an reconstruction of the Museum of Modern Art (MUO) in Denis street and building in a neighboring vacant lot. The proposal involves urban, architectural, operational layout, design and material solutions objects in spatial context. Within SEFO and MUO they are created each operation - stand-alone units. Objects SEFO and MUO are interconnected. It is necessary to respect the separation of publicly accessible areas of compartments accessible only by employees. Architectural study includes space for exhibitions, library, multi-purpose space with facilities, vestibule usable for exhibition openings and other cultural activities, chamber music performances, as well as facilities for education, technological facilities of the building, the depositary (transport and central), photo studio restoration studio, office space, locker rooms and restrooms personnel. SEFO specific aim of capturing the diverse manifestations of visual culture of Central Europe after World War 2, the building's permanent exhibition, acquisition activity, temporary exhibitions, including larger medium-shows (eg. The biennial or triennial), discussion forums and other supporting cultural events.